Charge syndrome is an autosomal dominant genetic disorder typically caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) gene. Inner ear abnormality is the most prevalent clinical feature associated with this disorder, as more than 90% of patients with CHARGE syndrome exhibit malformations of the inner ear structures accompanied by profound hearing loss. However, the mechanism by which mutations in CHD7 leads to the birth defects in CHARGE syndrome is poorly understood. Recent technological advancements in stem cell biology have made it possible to create induced pluripotent stem cells (iPSCs) from a small skin sample of patients with genetic disorders. These patient-derived iPSCs harbor the same genome predisposed to the disorder, and thus serve as a potent human model system to investigate disease-specific pathogenesis and potential therapeutic interventions. The goals of this application are (1) to generate iPSCs with skin fibroblasts isolated from patients with CHARGE syndrome and, using these patient- derived iPSCs, (2) to study disease progression by deriving otic neural progenitors in vitro, and (3) to identify inner ear-specific target genes for CHD7. Our long-term goal is to uncover how mutations in CHD7 cause dysregulated expression of a specific set of genes in the inner ear, resulting in inner ear anomalies and profound hearing loss. The proposed study will provide valuable information on the prenatal diagnosis and targeted treatment of this devastating congenital disorder.
CHARGE syndrome is a congenital disorder typically caused by mutations in the chromatin remodeling enzyme CHD7. Inner ear anomalies, such as auditory nerve dysfunction and semicircular canal hypoplasia, are the most prevalent clinical features associated with this genetic disorder. The goal of this study is to establish a human model system in order to clearly understand how mutations in CHD7 lead to inner ear malformations, accompanied by profound hearing loss and vestibular dysfunction, in patients with CHARGE syndrome.
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| Koehler, Karl R; Mikosz, Andrew M; Molosh, Andrei I et al. (2013) Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500:217-21 |
